Poly (ADP-ribose) polymerase (hereinafter, abbreviated as “PARP”, another name: poly (ADP-ribose) synthetase) is a protein that regulates the function of nuclear DNA, and an enzyme that is activated by recognizing the damage of DNA to successively transfer poly (ADP-ribose) to acceptor proteins such as DNA-polymerase, utilizing NAD (nicotinamide adenine dinucleotide) being an essential constitutive element in cell as an enzyme substrate. It is considered therefore that the excessive activation of PARP may cause decreased capacity of energy production in cell based on the depletion of NAD essential for the electron transport system and result in cell death (C. Szabo, Free Radic. Biol. Med., 21, 855(1996)). Moreover, PARP has also been attracting attention as an apoptosis-relevant enzyme from the fact that caspase-3, one of the interleukin-1b conversion enzyme-like protease family, cleaves PARP as substrate.
Furthermore, it is reported from an experiment using PARP-knockout mice that the cultured nerve cells obtained from the brain of the knockout mice exhibit resistance to the injury due to nitric oxide and excitatory amino acids such as NMDA (N-methyl-D-aspartate) and that in this knockout mouse, the infarction volume due to cerebral ischemia is reduced by about 80% or more (M. J. L. Eliassonetal., Nature Med., 3, 1089(1997)). From these facts, it is considered that the PARP inhibitor would be effective for cerebral infarction and neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson disease, etc.). Besides, there is a report that describes that it would be effective for diabetes, diseases due to ischemia or ischemia-reperfusion such as cardiac infarction and acute renal failure, circulatory diseases such as septic shock, and inflammatory diseases such as chronic rheumatism and multiple sclerosis (C. Szabo et al., Trend pharmacol. Sci., 19, 287(1998)). It is also reported that the PARP inhibitor would be effective as an antiretrovirus agent including HIV (G. A. Cole et al., Biochem. Biophys. Res. Commun., 180, 504(1991)) and a sensitizer for anticancer therapeutics (C. Arundel-Suto, et al., Radiat. Res., 126, 367 (1991); S. Boulton et al., Br. J. Cancer, 72, 849(1995)).
Based on the facts as above, it is expected that a compound with the PARP inhibitory activity is effective as a preventive and/or therapeutic drug for the diseases originating from excessive activation of PARP, for example, various ischemic diseases (cerebral infarction, cardiac infarction, acute renal failure, etc.), inflammatory diseases (inflammatory enteric disease, multiple cerebrosclerosis, arthritis, chronic rheumatism, etc.), nerve-degenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson disease, etc.), diabetes, septic shock, cephalic injury and the like.
There, as compounds with the PARP inhibitory activity known currently, formulae (A) to (P) listed in Table 1
TABLE 1Relevant PatentapplicationFormulaUS5756510(A) (B) (C) WO9704771(D) WO0121615(E) (F) WO0029384(G) WO0185687(H) WO9959973(I) WO0042025(J) JP2001302669(K) WO0179206(L) WO0014054(M) WO0170674(N) (O) (P)are known, but all of them are not isoquinolinone derivatives and have different structure from that of the inventive compounds. Moreover, the PARP inhibitory activities disclosed cannot also be said to be sufficient.
Moreover, as compounds having the isoquinolinone structure with the PARP inhibitory activity, in Jpn. Kokai Tokkyo Koho JP 002,124,874, compounds represented by a formula (Q)
(wherein R denotes OR1, lower alkyl group, NR1R2, halogen atom, trifluoromethyl group, COOX2, CN or COX2 (wherein R1 denotes a hydrogen atom, lower alkyl group, benzyl group, lower alkanoyl group or (CH2)n(CHOH)y(CH2)mA (wherein n denotes an integer of 1 to 4, y denotes an integer of 0 or 1, m denotes an integer of 0 to 5, A denotes OR2, N(CH3)2,
R2 denotes a hydrogen atom, lower alkyl group, phenyl group or benzyl group, and X2 denotes a lower alkyl group, aryl group or aralkyl group), X denotes independently OR1, S-alkyl group with C1˜4 or NR4R5 (wherein R4 and R5 denote each independently a hydrogen atom, lower alkyl group, benzyl group, lower alkanoyl group or (CH2)n(CHOH)y(CH2)mQ (wherein Q denotes N(CH3)2 or N(CH2CH3)2)), Z denotes —CHR2CHR3—, —CR6═CR3—or —CR3═N— (wherein R3 denotes a hydrogen atom, alkyl group, phenyl group or benzyl group, and R6 denotes a hydrogen atom, lower alkyl group, phenyl group, benzyl group, chlorine atom, bromine atom or NR7R8 (wherein R7 and R8 denote each independently a hydrogen atom or lower alkyl group)), and, when Z is —CR3═N—, N in Z is bound to N on ring), are known, and, in WO9911624, compounds represented by a formula (R)
(wherein X denotes a double bond oxygen atom or hydroxy group, R7 denotes a hydrogen atom or lower alkyl group, Y denotes independently an atom needed for forming monocyclic, bicyclic or tricyclic hydrocarbon ring consisting of 5- to 6-membered ring or condensed ring being a heterocycle, and Z denotes —CHR2CHR3— (wherein R2 and R3 denote each independently a hydrogen atom, alkyl group, aryl group or aralkyl group), —R6C═CR3— (wherein R3 and R6 denote each independently a hydrogen atom, lower alkyl group, aryl group, aralkyl group, halogen atom, —NO2, —COOR7 or —NR7R8 (wherein R8 denotes a hydrogen atom or C1˜C9 alkyl group), and R6 and R3 may constitute independently a 5- to 6-membered aromatic ring), —R2C═N—, —CR2 (OH) —NR7 or —C(O)—NR7—), are known. However, in the specifications of these patent applications, isoquinolinones with hydroxy group at 5-position and aryl group at 4-position, which is a feature of the inventive compounds, are not disclosed, and the PARP inhibitory activity of compounds disclosed in these cannot also be said to be sufficient.
Moreover, compounds represented by a formula (S) described in Table 2
TABLE 2(S) RelevantpatentapplicationR1, R2, R3, R4, R5 and R6US5516941R1, R2, R3, R4 and R5 denote each a hydrogen atom ornitroso group, either of R2 and R4 denotes a nitrosogroup, and R6 denotes a hydrogen atom.WO9218123R1, R2, R3, R4, R5 and R6 denote each independently ahydrogen atom, hydroxy group, amino group, alkyl group,alkoxy group, cycloalkyl group, halogen atom, phenylgroup or phenyl group which may be substituted with alkylgroup, alkoxy group, hydroxy group or halogen atom.WO9426730R1, R2, R3, R4 and R5 denote each independently ahydrogen atom, hydroxy group, amino group, nitrosogroup, nitro group, halogen atom, (C1–C6)alkyl group,(C1–C6)alkoxy group, (C3–C7)cycloalkyl group or phenylgroup, and, among R1, R2, R3, R4 and R5, at least twodenote each a hydrogen atom, one denotes a nitro group,and R6 denotes a hydrogen atom.WO9622791R1, R2, R3, R4 and R5 denote each independently ahydrogen atom, hydroxy group, nitroso group, nitro group,iodine atom, (C1–C6)alkyl group, (C1–C6)alkoxy group,(C3–C7)cycloalkyl group or phenyl group, and, amongR1, R2, R3, R4 and R5, at least two denote each ahydrogen atom, one denotes a nitroso group or nitro group,and R6 denotes a hydrogen atom.WO9851307R1, R2, R3, R4 and R5 denote each independently ahydrogen atom, hydroxy group, amino group, alkyl group,alkoxy group, cycloalky group or phenyl group which maybe substituted with alkyl group, alkoxy group, hydroxygroup or halogen atom, and, among R1, R2, R3, R4 andR5, at least one denotes an amino group, nitroso group ornitro group.WO9851308R1, R2, R3, R4 and R5 denote each independently ahydrogen atom, hydroxy group, amino group, alkyl group,alkoxy group, cycloalkyl group or phenyl group which maybe substituted with alkyl group, alkoxy group, hydroxygroup or halogen atom, and, among R1, R2, R3, R4 andR5, at least one denotes an amino group.are known, but the isoquinolinone derivatives disclosed in the specifications of these patent applications are only 5-nitrosoisoquinolinones, and there are no descriptions with respect to the isoquinolinone derivatives with hydroxy group at 5-position and aryl group at 4-position, which is a feature of the inventive compounds.
Furthermore, as structure-resemblant compounds with the PARP inhibitory activity, in WO0044726, compounds represented by a formula (T)
[wherein R1 denotes a C1˜4 alkyl group substituted with hydroxy group or amino group, or -A1-A2-A3 (wherein A1 denotes —NR3C(O)—, —NR4C(S)—, —NR5SO2— or the like, A2 denotes a C1˜8 alkylene group, C2˜8 alkenylene group, Cyc1 or the like, and A3 denotes a hydrogen atom, —NR17R18, Cyc2, —OR19 or the like)] (a part was extracted for the explanation of substituents), and, in WO0067734, compounds represented by a formula (U)
[wherein R1 denotes a hydrogen atom, halogen atom, straight chain or branched C1-C6-alkyl group, hydroxy group, nitro group, CF3, CN, NR11R12, NH—CO—R13 or O—C1-C4-alkyl group (wherein R11 and R12 denote each independently a hydrogen atom or C1-C4-alkyl group, and R13 denotes a hydrogen atom, C1-C4-alkyl group, C1-C4-alkyl-phenyl group or phenyl group), A1 denotes a straight chain or branched C0—C6-alkylene group, A2 denotes NR2, NR2-C1-C6-alkyl-, O or the like, and A3 denotes a 5- to 6-membered monocyclic or bicyclic aromatic ring which may have substituents or hetero aromatic ring] (a part was extracted for the explanation of substituents), are known, but all of these are phthalazinone derivatives, hence the structure is different from that of the inventive compounds being isoquinolinone derivatives. In addition, no compounds with hydroxy group at a portion corresponding to 5-position of isoquinolinone, that is, at 5-position of phthalazinone are disclosed.
Moreover, as structure-resemblant compounds of 4-substituted aryl-5-hydroxyisoquinolinone derivatives, in U.S. Pat. No. 4,897,391, as compounds with antiallergy, anti-inflammation and inhibitory effect on abnormal proliferation, compounds represented by a formula (V)
[wherein R1 denotes a hydrogen atom, alkyl group, arylmethyl group or the like, R2 denotes a hydrogen atom, alkyl group, aryl group or the like, R3 denotes a hydrogen atom, alkyl group, arylmethyl group, aryl group or the like, R4 and R6 denote each independently a hydrogen atom, halogen atom, —OR8 (wherein R8 denotes independently a hydrogen atom or alkyl group) or the like, and, between R4 and R6, at least one denotes —SH, —OH, —NHR8 or the like, and R5 and R7 denote each independently a hydrogen atom, halogen atom, —CF3 or the like] (a part was extracted for the explanation of substituents), are known, but all of the compounds described in the specification of this patent application have the same substituents at 5-position and 7-position of isoquinolinone ring, and no compounds with hydroxy group only at 5-position as the inventive compounds do are disclosed. In addition, it is difficult to prepare the compounds with hydroxy group only at 5-position as the inventive compounds through the preparative process disclosed. Further, also with respect to aryl group at 4-position, only phenyl group is disclosed and phenyl group having substituents and hetero aryl group is not disclosed. Also, the PARP inhubitory activity is not described at all.
Moreover, compounds represented by a formula (W) described in Table 3
TABLE 3(W) RelevantpatentapplicationRing A, ring B and REffectJP05132463Ring A and ring B are benzene ringsACATwhich may have substituents, and Rinhibitoryis NHCO—Y—R2.effectJP06321906Ring A and ring B are benzene ringsAntagonismwhich may have substituents, and R isagainsttachykinin JP0776573Ring A and ring B are benzene ringsInhibition ofwhich may have substituents, and R iscalcium(CH2)m—X—CO—Y—(CH2)n—Ar.release,protection ofcerebralischemicdisorder, anti-cerebral edema,protection ofnervousdisorder,antagonismagainsttachykininJP10298164Ring A and ring B are benzene ringsPDE Vwhich may have substituents, and R isinhibitory—COOR3 or —CON(R4)(R5).effectJP200072675Ring A and ring B are benzene ringsPDE Vwhich may have substituents, and R isinhibitory—COOR3 or —CON(R4)(R5).effectare known, but compounds with substituent other than hydrogen atom at 2-position and hydroxy group at 5-position as well are not disclosed in all cases, hence the structure is different from that of the inventive compounds. Alao, the PARP inhibitory activity is not described at all.
The invention is to provide a novel compound with PARP inhibitory activity, the development of which is expected as a preventive and/or therapeutic drug for the diseases originating from excessive activation of PARP, for example, various ischemic diseases (cerebral infarction, cardiac infarction, acute renal failure, etc.), inflammatory diseases (inflammatory enteric disease, multiple cerebrosclerosis, arthritis, chronic rheumatism, etc.), nerve-degenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson disease, etc.), diabetes and its complications, cephalic injury and the like.